Role of an Epithelial Ets Factor in Breast Cancer

上皮 ETS 因子在乳腺癌中的作用

• 批准号: 6767567
• 负责人: Dennis K Watson
• 金额: $ 28.09万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6767567
• 关键词: breast neoplasms; cell line; cell migration; cell motility; clinical research; female; gene expression; genetically modified animals; human subject; laboratory mouse; metastasis; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic process; oncogenes; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The long-term goal of this project is the elucidation of the mechanisms whereby Ets upstream effectors and downstream target genes contribute to progression to invasive breast cancer. Breast cancer is the second leading cause of cancer mortality in women. Unfortunately, little is known about the most devastating phase of its progression, metastasis. To metastasize, cells acquire topic motility and invasiveness as well as the ability to proliferate in a new microenvironment. Metastasis is a multi-step process, including breaking loose from cell-cell contacts, migrating through stromal tissues, invading endothelial cell layer, re-establishing and maintaining cell contacts at the metastatic site, remaining proliferative. Recently, a novel ETS factor, PDEF, was cloned and initially reported to be specific to prostate epithelium q2rostate derived ets factor). Our work has demonstrated that PDEF is expressed in several additional epithelial tissues including breast and colon. We also show that PDEF protein loss is correlated with prostate, colon and breast cancer progression. To support the model that PDEF has a central role in modulating metastatic potential, we have demonstrated that PDEF protein expression is lost in highly metastatic cell lines and in invasive breast tumor tissues. Re-expression of Pdef into invasive cancer cells inhibits cell growth. Mouse Pdef is down-regulated in tumors in Neu transgenic mice. Pdef activates the tumor metastasis suppressor maspin while downregulating the metastasis promoter uPA. The Drosophila PDEF homolog is a negative modulator of cell migration and invasion during development. Thus, our observations lead us to propose that PDEF, as a transcription factor, controls multiple aspects of the multistep metastatic process and therefore, loss of PDEF expression is a key event in the development of invasive breast cancer. In this proposal, we employ a comprehensive strategy to elucidate PDEF function, integrating four in vitro and in vivo experimental systems. (1) Cell culture for studying cellular phenotypes associated with PDEF expression levels and for identifying downstream effectors of PDEF functions. (2) Mouse knockout and transgenic systems for analyzing the role of the Pdefgene in mammary development and cancer. (3) The Drosophila system to investigate the function of Pdef in cell migration/invasion in vivo. (4) Human breast tumor samples for correlating expression of PDEF and its effectors with cancer progression.

描述（由申请人提供）：本项目的长期目标是阐明Ets上游效应子和下游靶基因促进浸润性乳腺癌进展的机制。乳腺癌是妇女癌症死亡的第二大原因。不幸的是，很少有人知道它的发展，转移的最具破坏性的阶段。为了转移，细胞获得局部运动性和侵袭性以及在新的微环境中增殖的能力。转移是一个多步骤的过程，包括从细胞-细胞接触中挣脱，通过基质组织迁移，侵入内皮细胞层，在转移部位重建和维持细胞接触，保持增殖。最近，一种新的ETS因子PDEF被克隆，并首次报道其对前列腺上皮细胞具有特异性。我们的工作表明，PDEF表达在几个额外的上皮组织，包括乳腺和结肠。我们还发现PDEF蛋白丢失与前列腺癌、结肠癌和乳腺癌的进展相关。为了支持PDEF在调节转移潜能中具有核心作用的模型，我们已经证明PDEF蛋白表达在高转移性细胞系和侵袭性乳腺肿瘤组织中丢失。Pdef在侵袭性癌细胞中的再表达抑制细胞生长。小鼠Pdef在Neu转基因小鼠的肿瘤中下调。Pdef激活肿瘤转移抑制因子maspin，同时下调转移促进因子uPA。果蝇PDEF同源物是发育过程中细胞迁移和侵袭的负调节剂。因此，我们的观察使我们提出，PDEF，作为一种转录因子，控制多个方面的多步转移过程，因此，PDEF表达的损失是一个关键事件，在浸润性乳腺癌的发展。在这个提议中，我们采用了一个全面的策略来阐明PDEF功能，整合了四个体外和体内实验系统。(1)用于研究与PDEF表达水平相关的细胞表型和用于鉴定PDEF功能的下游效应物的细胞培养物。(2)用于分析Pdef基因在乳腺发育和癌症中的作用的小鼠敲除和转基因系统。(3)果蝇系统研究Pdef在体内细胞迁移/侵袭中的功能。(4)用于将PDEF及其效应物的表达与癌症进展相关联的人乳腺肿瘤样品。